Monday, 6 February 2017

Is MS a T cell-Mediated disease

We made a suggestion that the B memory cell was important in MS. http://multiple-sclerosis-research.blogspot.com/2017/02/ms-is-b-cell-disease-and-memory-b-cells.htmlCLICK TO READHowever, the reviewer was spitting blood that we did not mention T cells enough times and thought that the review was a bit biased.Sure it has biased...as it is any opinion piece. If we did not take a stance, it could become a love-in and we would say everything is because of T cells.....no-one would bat an eyelid and we would keep on developing T cell treatments that have been pretty poor at controlling MS, but very good at treating EAE.There were more than enough references compared to the 75 limit and to give a T cell-centric opinion on all treatments to appease someone, who frankly was never going to listen, or change or question their own pre-conceptions.Sure all MS drugs affect T cells in some way, but we need to be abit more specific than that, as we know that the level of CD4 and CD8 depletion does not associate with relapses. However, we believe that the disease causing cells must be antigen activated (i.e. in the primed CD45RO positive) T cell pool. See last weeks post as this is the basis for this post.http://multiple-sclerosis-research.blogspot.com/2017/02/rebound-after-natalizumab-show-memory.htmlHowever to make the referee happier we should have gone through the treatments one by one, to do the same type of search that we did to look for memory B cell activity, as we were asked to do by a blogger.

T cells likewise have T cell memory cells.Therefore, we took the view that the T cells harboring the pathogenic cells would be in the CD4 or CD8 population that express CD45RO (a memory marker) and do not express CD45RA (antigen-inexpertienced cell marker) or CD62L (an adhesion molecule involved in getting cells into the lymph nodes) but express high levels of CD44 (to get the T cells into tissues including the brain. If you accept this, some won't so please read this recent post, then the important pathogenic cells will reside within the effector memory T cell population and not the naive or central memory T cell populations (CCR7+)We then went through the current MS drugs and see how blood levels correlate with the idea that MS is associated with effector memory T cell levles. We searched on the "name of the drug" and "CD45RO/memory T cell" just like we had searched on "CD27/memory B cell".The search revealed a positive correlation of B memory cell function with all MS drugs and was this was most clear in the highly active DMT.Sure these drugs can affect T cells, but what about effects on the memory cells.If we take the same argument for T memory cells, what do we get?_____________________________________________ CD4 memory T CD19, CD27 memory B_____________________________________________Alemtuzumab NO YESAnti CD20 NO YESNatalizumab NO YESMitoxantrone NO YESDaclizumab MARGINAL NO YES MarginalDMF YES YES Beta Interferon YES/NO YESCopaxone NO YES _____________________________________________ Noooooooooooooooooooooooooo...it can't be says MrT.

There are a few T cells that get depleted, but the T cell population doesn't go down enough to suggest there was any effect of the memory T cell subset. So no direct effect on T cells can be linked to T cell number...Next

Fingolimod-NO Expect decrease in memory T cells if importantAs we would expect the cells expressing CCR7 are trapped in the lymph glands and the effector memory population increases. So the T cell idea is not very compelling when looking in the bloods of people treated with the highly active drugs.

Copaxone-NOExpect decrease in memory T cells if importantLastly the drug that has had every mechanism under the sun:-), but maybe not this one as....Yikes it does nothing or makes the number of memory T cells go up.

The hypothesis was that BAFF makes autoimmunity worse and makes a Th1 response. A transgenic mouse making BAFF made more Th17 and EAE was a little worse, where as BAFF knockout mice made fewer Th17 and was a little better and got EAE despite having no B cells. So problem when you do experiment, before you know the result, you don't always get what happens in MS.

Next follow-up and TACI-Ig (atacicept) causes a decrease in Th1 and Th17, so wrong way to explain MS result using a Th1/Th17 idea but low and behold there was an increase in memory T cells.

So if I presented this to the referee as the other half of the story would they buy it? Would they block the B cells stuff to Ensure the T cell stuff is never read? Would it have been worth the extra few references?What references do we need to add contradict this view?

Would someone publish this? Would the referee accept that their bubble bursts?

10 comments:

I've been with you on the memory B cells (child's been on Rituxan 3.5 years with spectacular turnaround), but appreciate all the time and effort put into this.Perhaps it will do some good, at least for patients and students. I suspect some researchers are firmly wedded to their "truths", and will ignore.

This B-cell theory is very compelling MD in RRMS/inflammation. Thanks for your passionate & hard work in presenting and congratulations on your publication.

The problem that I see is that none of the above drugs effectively stop the progression of MS whatsoever. What is the use of comparing any of these drugs if they do not effectively halt the progression of the disease? Obviously, the B-cell theory is important in relapses/inflammation, but it appears but something else is causing progression of the disease (A1 astrocytes, hot microglia or neuronal cellular dysfunction) to which B-cells (or T-cells) seemingly play a much smaller role.

Maybe... maybe not, if I say that B cells enter CNS and form the B cell follicles and plasma cells and they secrete antibody and make cytokines and these antibodies attack the nerves or they activate the microglial that then make the A1 astrocytes that damage the demyelinated nerves, but they are not blocked because none of the current licenced DMT get into the CNS to target the B cells...can you argue against this?

We have repeated said that we need to target multple componenets to target damaging elements of MS.

What happens when we use the big gun agents early in MS.

Likewise how do we target cells in the CNS, the approach of using antibodies is not the way to go they just dont get in..

A combination is likely to be the best option but pharma dont like combinations but look at HIV for example, it use to be a death sentance but with a poly pill the virus can be held at bay for many people.

To answer your question, there may be some advantage because unlike and drug it can get into the CNS, about a quarter of the blood levels, it does not need cell division to act unlike cyctostatic drugs, and it has the potential to kill plasma cells and it may reduce OCB in some people. This needs further study.

Any thoughts if this article could show a possible way T cells still could be the cause: MNT : T cell type that promotes damaging immune response discoveredhttp://www.medicalnewstoday.com/articles/315627.php

For T cells there is a subpopulation of cell labeled Follicular B helper T cells https://en.wikipedia.org/wiki/Follicular_B_helper_T_cells

These help B cells produce antibody..what this study is saying is that there is a subset of T cells they call peripheral peripheral helper' found in the joint that help B cells to produce antibody. However central problem is the B cells and the T cell facilitates. Immunology works in tandem so it it is not going to be one or the other but both.

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